Process for the preparation of repaglinide

ABSTRACT

The present invention relates to a cost effective and industrially advantageous process for the preparation of repaglinide.

FIELD OF THE INVENTION

The present invention relates to a cost effective and industriallyadvantageous process for the preparation of repaglinide.

BACKGROUND OF THE INVENTION

Chemically, repaglinide isS(+)-2-ethoxy-4-[N-{1-(2-piperidinophenyl)-3-methyl-1-butyl}aminocarbonylmethyl]benzoicacid having the Formula I,

and is known from U.S. Pat. No. 5,312,924. It belongs to a new class ofhypoglycemic benzoic acid derivatives. It offers significantly betterbiological profile as compared to sulphonylurea class of compounds forthe treatment of non-insulin dependent diabetes mellitus (NIDDM).

U.S. Pat. No. 5,312,924 describes a process for the preparation ofrepaglinide which involves the reaction of (S)-amine of Formula II,

with a carboxylic acid of Formula III,

wherein W represents a (protected) carboxy group or a reactivederivative thereof, and cleaving the protecting group, if necessary, toobtain repaglinide of Formula I.

The reaction of the (S)-amine of Formula II with a carboxylic acid ofFormula III is carried out in the presence of N,N′-carbonyldimidazole,N,N′-dicyclohexylcarbodiimide or triphenylphosphine/carbon tetrachlorideand triethylanmine. N,N′-carbonyldimidazole is expensive and gives lowyields (50 to 55%) while the use of triphenylphosphine/carbontetrachloride necessitates chromatographic purification to obtainrepaglinide of desired purity. The use of N,N′-dicyclohexylcarbodiimidegenerates dicyclohexyl urea as a by-product which can only be removed byrepeated crystallizations of the product resulting in increased cycletime and the cost of production. Furthermore, theN,N′-dicyclohexylcarbodiimide is toxic and its use on a commercial scaleis undersirable.

Several variations of this method are known which involve thecondensation of differently substituted amines and carboxylic acids,followed by suitable chemical modification of the substituents to obtainrepaglinide. All of these variations involve additional number ofsynthetic steps and are therefore not suitable for commercial scaleproduction of repaglinide.

It is, therefore desirable to solve the problems associated with theprior art and to provide an efficient process for the preparation ofrepaglinide which process improves the economics by employing lessexpensive and less hazardous raw materials and is more productive. Theprocess avoids the tedious and cumbersome procedures of chromatographyor special recrystallization techniques, is economical and convenient tooperate on a commercial scale.

The present invention provides a process for the preparation ofrepaglinide of Formula I comprising:

a) reacting the (S)-amine of Formula II with a protected carboxylic acidof Formula IV,

-   -   wherein R is a protecting group, in the presence of pivaloyl        chloride and a base, and

b) removing the protecting group to obtain repaglinide.

The protecting group R in the compound of Formula IV is any carboxylicacid protecting group which is easily removed, such as methyl, ethyl,tert.-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, and the like.

The reaction is carried out in the presence of a suitable base which maybe either organic or inorganic. Examples of suitable organic basesinclude amines such as diisopropylamine, dicyclohexylamine,1,8-diazabicyclo[5.4.0] undec-7-ene, triethylamine, tributylamine,N,N-dimethylaniline, diisopropylethylamine, and the like. Suitableinorganic bases include potassium carbonate, sodium carbonate, and thelike.

The reaction may be carried out in a suitable solvent such asdichloromethane, toluene, xylene, and the like. The reaction is carriedout at temperatures of between −25° C. and 40° C., but preferably attemperatures of between −10 and 25° C.

The removal of a carboxylic acid protecting group is achieved bysuitable methods known in the art such as acidic or basic hydrolysis orhydrogenolysis.

DETAILED DESCRIPTION OF THE INVENTION

In the following section one preferred embodiment has been described byway of example to illustrate the process of the invention. However, itis not intended in any way to limit the scope of the present invention.

EXAMPLE

Preparation of ethyl(S)-2-ethoxy-4-[N-{1-(2-piperidinophenyl)-3-methyl-1-butyl}aminocarbonylmethyl]benzoate

Pivaloyl chloride (5.4 g, 45 mmol) was added to a mixture of3-ethoxy-4-ethoxycarbonyl phenylacetic acid (10.0 g, 40 mmol), toluene(50 ml) and triethylamine (5.0 g, 49 mmol) at −5° C. and stirred for 1hour. A solution of (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine(9.8 g, 40 mmol) in toluene (20 ml) was then added at below 10° C. Thetemperature of the reaction mixture was raised to 30° C. and the mixturestirred overnight. It was then washed with water and saturated sodiumbicarbonate solution. Toluene was distilled off under reduced pressureto get the crude product. The crude product was dissolved in toluene (35ml), hexane (200 ml) was added and the mixture cooled at 0° C. The solidproduct so obtained was filtered and dried to give 14.0 g of the titlecompound (Yield: 73%, HPLC Purity 99%).

Preparation of(S)-2-ethoxy-4-[N-{1-(2-piperidinophenyl)-3-methyl-1-butyl}aminocarbonylmethyl]benzoicacid

A solution of ethyl(S)-2-ethoxy-4-[N-{1-(2-piperidinophenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]benzoate(20 g, 41.6 mmol) in denatured spirit (200 ml) was stirred at 60–65° C.and 1N sodium hydroxide solution (62 ml) was added. After two hours ofstirring at 60° C., the reaction mixture was cooled to 35° C. and pH wasadjusted to about 5.0 using 1N hydrochloric acid (about 70 ml). Thesolution was stirred for 30 minutes at 35–40° C., cooled to 0° C. andstirred at 0 to 5° C. for one hour to get a crystalline product. Thecrystals were separated by filtration and washed with water. The productwas dried at 60–65° C. under vacuum to get repaglinide (17.8 g, Yield:94%, Assay 99.5% by HPLC).

While the present invention has been described in terms of its specificembodiments, certain modifications and equivalents will be apparent tothose skilled in the art and are intended to be included within thescope of the present invention.

1. A process for the preparation of repaglinide of Formula I,

comprising: a) reacting the (S)-amine of Formula II,

with a protected carboxylic acid of Formula IV,

wherein R is a protecting group, in the presence of pivaloyl chlorideand a base, and b) removing the protecting group to obtain repaglinide.2. The process according to claim 1 wherein the protecting group R isselected from the group consisting of methyl, ethyl, tert.-butyl,benzyl, p-nitrobenzyl, and p-methoxybenzyl.
 3. The process according toclaim 1 wherein the reaction is carried out in the presence of anorganic or inorganic base.
 4. The process according to claim 3 whereinthe organic base is an amine.
 5. The process according to claim 4wherein the amine is selected from the group consisting of1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, tributylamine,N,N-dimethylaniline, diisopropylethylamine diisopropylamine, anddiscyclohexylamine.
 6. The process according to claim 3 wherein theinorganic base is potassium carbonate or sodium carbonate.
 7. Theprocess according to claim 1 wherein the reaction is carried out in asolvent.
 8. The process according to claim 7 where the solvent isselected from the group consisting of dichloromethane, toluene andxylene.
 9. The process according to claim 1 wherein the reaction iscarried out temperatures of between −25° C. and 40° C.
 10. The processaccording to claim 9 wherein the temperature is −10° to 25° C.